10 years, 10 papers: building fundamental science and friendship
“This is by far the most productive collaboration I’ve ever had,” smiles Dr. Jeffrey Lee, “and it’s been really fun. Our friendship goes beyond the collaboration”.
The two basic scientists met not long after Lee joined LMP in 2010. With labs near each other in the Medical Sciences Building, the two would meet in the corridor and discuss ideas until Ohh reached out one day in 2012 to ask Lee to help him tackle a problem.
Ohh is a basic scientist who asks cancer-related questions. He studies the growth of cells and how they are affected by cancer by looking at mutations in major cancer-associated proteins. These include KRAS, which drives cell growth and division, and VHL, which regulates the oxygen sensing pathway.
Lee’s specialization is in crystallography, a type of structural biology, where he studies the atomic structure of proteins and enzymes. Through these techniques, his lab can create blueprints of proteins which help Ohh understand the structural implications of the various cancer-causing mutations.
“Our work involves a basic science question with clinical implications, utilizing molecular biology, biochemistry and structural biology. We came together to ask hard and interesting questions and it has been pretty cool so far”, says Ohh.
For example, in the hereditary syndrome called von Hippel-Lindau (VHL) disease, mutations in the VHL gene result in tumors arising in multiple organs. VHL disease has a very complicated and wide phenotypic presentation varying from patient to patient depending on the type of mutation an individual carries. However, no one knew why or how certain mutations resulted in certain cancers. Ohh realized they needed a 3-dimensional structure of VHL and the protein it interacts with, called HIF2. He worked with Lee to crystallize the VHL-HIF2 structure, the first lab in the world to do so. “Knowing this detail at an atomic level enabled us to figure out why certain mutations give rise to certain characteristics in this disease”, explains Ohh.
The pair have never shared a grant but have co-supervised students. “We’ve had some very talented trainees over the last 10 years who have driven a lot of these projects” says Lee. Their students would often drop in and out of the two labs to conduct experiments - something that was easy when they were in the same corridor, but still possible after Ohh moved his lab into the MaRS building across the street.
Curiosity-driven and fascinated by the biology, both bring enthusiasm and a similar mind-set to the partnership. Collaborations often fail due to varying commitments and expectations but Lee and Ohh “see eye-to-eye” as their motivations and standards are aligned. “We also like each other”, laughs Lee, “that definitely helps.”
“We have different techniques that complement each other for the projects and the questions we want to ask, which makes what we do so powerful. I create a model through crystallography and Mike does assays using cell-based systems and has the clinical data that fits it all together. Everything is black and white, there are no grey areas - fitting together beautifully, it’s elegant and the project has progressed very well over the last 10 years,” says Lee.
“What I’m proud of is the quality of the work we’ve produced together”, says Ohh, “we’ve advanced knowledge that will stand the test of time. We’ve also contributed significant foundational knowledge that will aid in precision medicine, which will result in more positive outcomes for patients”.
What makes their partnership really stand out is the rigor they apply to everything they do.
“We have a responsibility as basic researchers to produce the highest quality science that can stand the test of time”, explains Ohh. “Others will follow in our footsteps or take our discoveries and build on them. What we do has to be accurate. It’s ok to be wrong sometimes, science is always evolving, but we need to make sure we have produced our very best work. If the foundations aren’t solid, what’s built on top will fail. As my mentor used to say, ‘build houses of brick, not mansions of straw’.”
See also Pinpointing a Genetic Change: Study reveals how a genetic change in the KRAS gene can make cancer resistant to therapy on UHN Research News
Papers from the Ohh and Lee collaboration
Their 10th paper has just been submitted for publication.
The Q61H mutation decouples KRAS from upstream regulation and renders cancer cells resistant to SHP2 inhibitors. Nature Communications, 2021. Gebregiworgis T, Kano Y, St-Germain J, Radulovich N, Udaskin ML, Mentes A, Huang R, Poon BPK, He W, Valencia-Sama I, Robinson CM, Huestis M, Miao J, Yeh JJ, Zhang ZY, Irwin MS, Lee JE, Tsao MS, Raught B, Marshall CB, Ohh M, Ikura M.
HIF-1α Hydroxyprolines Modulate Oxygen-Dependent Protein Stability Via Single VHL Interface With Comparable Effect on Ubiquitination Rate. Journal of Molecular Biology, 2021. He W, Batty-Stuart S, Lee JE, Ohh M.
Evolution of metazoan oxygen-sensing involved a conserved divergence of VHL affinity for HIF1α and HIF2α. Nature Communications, 2019. Tarade D, Lee JE, Ohh M.
Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation. Nature Communications, 2019. Kano Y, Gebregiworgis T, Marshall CB, Radulovich N, Poon BPK, St-Germain J, Cook JD, Valencia-Sama I, Grant BMM, Herrera SG, Miao J, Raught B, Irwin MS, Lee JE, Yeh JJ, Zhang ZY, Tsao MS, Ikura M, Ohh M.
HIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease. Nature Communications, 2018. Tarade D, Robinson CM, Lee JE, Ohh M.
New structural and functional insight into the regulation of Ras. Seminars in Cell & Developmental Biology, 2016. Kano Y, Cook JD, Lee JE, Ohh M.
Oxygen-dependent Regulation of Erythropoietin Receptor Turnover and Signaling. Journal of Biological Chemistry, 2016. Heir P, Srikumar T, Bikopoulos G, Bunda S, Poon BP, Lee JE, Raught B, Ohh M.
Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation. Proceedings of the National Academy of Sciences (PNAS), 2014
Bunda S, Heir P, Srikumar T, Cook JD, Burrell K, Kano Y, Lee JE, Zadeh G, Raught B, Ohh M.
DCNL1 functions as a substrate sensor and activator of cullin 2-RING ligase. Molecular and Cellular Biology, 2013. Heir P, Sufan RI, Greer SN, Poon BP, Lee JE, Ohh M.